Biosynchronous transdermal drug delivery

ABSTRACT

Systems and methods for synchronizing the administration of compounds with the human body&#39;s natural circadian rhythms and addiction rhythms to counteract symptoms when they are likely to be at their worst by using an automated and pre programmable transdermal or other drug administration system.

This application claims the benefit of U.S. Provisional Application No.60/609,418 filed on September 13, 2004 which is incorporated herein byreference. This application also relates to PCT application No.PCT/IB2004/002947 entitled Transdermal Drug Delivery Method and Systemfiled on Sep. 13, 2004 which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates, in general, to controlled drug deliverymethods and systems, and, more specifically, to systems and methods forbiosynchronous transdermal drug delivery in which drugs,pharmaceuticals, and other bioactive substances are deliveredtransdermally into a body in a manner that is synchronized withbiological processes and/or biological rhythms so as to improveperformance of the substance in the body.

RELEVANT BACKGROUND

In the field of drug delivery, it is recognized that supplying the drugin a correct temporal pattern is an important attribute of any drugdelivery methodology. Controlled release drug delivery systems areintended to improve response to a drug and/or lessen side effects of adrug. The term “controlled release” refers generally to deliverymechanisms that make an active ingredient available to the biologicalsystem of a host in a manner that supplies the drug according to adesired temporal pattern. Controlled release drug delivery may beimplemented using instantaneous release systems, delayed releasesystems, and sustained release systems. In most cases, controlledrelease systems are designed to maintain a sustained plasma level of anactive ingredient in a drug within a human or animal host over a periodof time.

Instantaneous release refers to systems that make the active ingredientavailable immediately after administration to the biosystem of the host.Instantaneous release systems include continuous or pulsed intravenousinfusion or injections. Such systems provide a great deal of controlbecause administration can be both instantaneously started and stoppedand the delivery rate can be controlled with great precision. However,the administration is undesirably invasive as they involveadministration via a puncture needle or catheter. ‘Delayed release’refers to systems in which the active ingredient made available to thehost at some time after administration. Such systems include oral aswell as injectable drugs in which the active ingredient is coated orencapsulated with a substance that dissolves at a known rate so as torelease the active ingredient after the delay. Unfortunately, it isoften difficult to control the degradation of the coating or encapsulantafter administration and the actual performance will vary from patientto patient. Sustained Release generally refers to release of activeingredient such that the level of active ingredient available to thehost is maintained at some level over a period of time. Like delayedrelease systems, sustained release systems are difficult to control andexhibit variability from patient to patient. Due to the adsorptionthrough the gastrointestinal tract, drug concentrations rise quickly inthe body when taking a pill, but the decrease is dependent on excretionand metabolism, which can not be controlled. In addition, the adsorptionthrough the gastrointestinal tract in many cases leads to considerableside effects (such as ulcers), and can severely damage the liver.

Transdermal drug delivery has developed primarily for sustained releaseof drugs in situations where oral sustained release systems areinadequate. In some cases, drugs cannot be effectively administeredorally because the active ingredients are destroyed or altered by thegastrointestinal system. In other cases the drug may be physically orchemically incompatible with the coatings and/or chelating agents usedto implement sustained release. In other cases a transdermal deliverysystem may provide sustained release over a period of days or weekswhereas orally administered drugs may offer sustained performance overonly a few hours. A wide variety of active substances can be deliveredthrough transdermal systems so long as the active substance can beprovided in a form that can cross the skin barrier.

In most cases transdermal delivery systems are passive, taking the formof a patch that is adhesively attached to the host. The patch includes aquantity of the active substance, along with a suitable carrier if needbe, absorbed in a sponge or similar system. Once applied, the activeingredient diffuses into the host through the skin at a rate determinedby the concentration of the active substance and the diffusivity of theactive substance. However, a variety of physical and chemical processesat the skin/patch boundary affect the delivery rate and may eventuallyinhibit drug delivery altogether. Active transdermal delivery systemshave been developed to help regulate the delivery rate by providingmechanisms to improve drug delivery over time by “pumping” the activeingredient. One such system is described in U.S. Pat. No. 5,370,635entitled “DEVICE FOR DELIVERING A MEDICAMENT” which describes a systemfor delivering a medicament and dispensing it to an organism for arelatively long period of time, for example at least a few days. Thedevice can be adapted for positioning on the surface of the skin of ahuman or possibly an animal body in order to apply a medicament theretofrom the outer side thereof.

Conventional transdermal systems circumvent the disadvantages of theadsorption through the gastrointestinal tract, but they do not optimizeor tailor the dosing regiment to offset peak symptoms. In addition theconstant transdermal delivery of a drug can lead to severe side effects,including debilitating sleep disorders and ever increasing tolerance.

Timed delivery is most often used to maintain a sustained level of adrug in the body. A significant focus of current research in drugdelivery has been to determine the influence of a patient's circadian orother biological rhythms on drug efficacy and efficiency. This researchdemonstrates that certain disease symptoms follow a daily pattern, withpeak symptoms at certain times of the day. It has been widelyacknowledged that hormones, neurotransmitters and other intra-bodycompounds are released in different amounts at different times of theday pursuant to daily patterns. The Wall Street Journal reported on May27, 2003 that ‘Doctors are increasingly looking at the clock when itcomes to prescribing medicine, instructing patients not only to whatdrug to use but also precisely when to take it. The new approach stemsfrom a growing body of research that demonstrates that certain diseasestend to get worse at certain times of the day, By synchronizingmedications with a patient's body clock, many physicians believe thatthe drugs will work more effectively and with fewer side effects. Insome cases, the improvements have been so pronounced that doctors havebeen able to reduce dosages.” Similarly, American Pharmacy reports that‘Circadian physiologic processes alter drug absorption, distribution,metabolism, and excretion. As a result, drug doses need to be adjustedto meet the differing needs of target organs or tissues at various timesof the day. See, L. Lamberg, American Pharmacy, 1991; N831(11): 20-23.Doctors have responded to this growing body of research by prescribing acarefully timed drug administration regimen to optimize treatment.

Recently, an orally administered drug for arthritis treatment hassuggested a chronotherepeutic approach using a delay release systemwhere the delay is scheduled to release the active ingredient at thebeginning of an interleukin 6 cascade that is believed to cause earlymorning stiffness in rheumatoid arthritis patients. By attempting tosynchronize the drug delivery with a biological cycle it is believedthat low doses may be used to achieve desired results. However, thissystem does not overcome the limitations of delayed release systemsdescribed above. Although it is possible to meet the requirements ofchronopharmacology with pills, this requires an enormous amount ofdiscipline by the patient to comply with the treatment regiment. Asillustrated above, to achieve optimal results, many patients may need towake up during the night to take their medication.

Hence, what is needed is a reliable means of delivering multiple drugsin precisely timed and measured doses-without the inconvenience andhazard of injection, yet with improved performance as compared toorally-delivered drugs.

Currently, patient compliance (taking the proper dosages at theprescribed times) is a critical problem facing caregivers andpharmaceutical firms alike. Studies show that only about half ofpatients take medications at the times and in the dosages directed bytheir physician. It is reported that each year, 125,000 deaths and up to20% of all hospital and nursing home admissions result from patient noncompliance. It is estimated that non-compliance results in additionalhealthcare costs in excess of $100 billion per year in United States.These figures are even more pronounced for the elderly. Hence, a needexists for systems and methods that increase patient compliance foradministration of a variety of drugs.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

SUMMARY OF THE INVENTION

Briefly stated, the present invention involves synchronizing theadministration of compounds with the human body's natural circadianrhythms and addiction rhythms to counteract symptoms when they arelikely to be at their worst by using an automated and pre programmabletransdermal or other drug administration system.

Specifically, this invention describes a method to maximize theefficiency of compound administration, decrease negative side effectsand increase the efficacy of pharmacological therapy by synchronizingand tailoring the administration of certain compounds to match thesecircadian rhythms.

Thus based on an analysis of the human body's circadian rhythms, theinvention delivers varying dosages at varying times, pursuant to apre-programmed dosage profile. This ensures that peak drugconcentrations are present in the bloodstream to offset peak disease andaddiction symptoms arising from variances and fluctuation in the body'snatural circadian rhythms. Further, these methods ensure that less of adrug is in the bloodstream when disease and addiction symptoms are atthere lowest.

The present invention describes methods for treating diseases,addictions and disorders in humans. These methods involve synchronizingand tailoring the administration of compounds with the body's naturalcircadian rhythms to counteract symptoms when they are likely to be attheir worst by using an automated and pre programmable transdermal drugadministration system.

More specifically, these methods synchronize and tailor drugadministration to the human body's circadian rhythms to deliver varyingdosages at varying times. This ensures that peak drug concentrations arepresent in the bloodstream to offset peak disease and addiction symptomsarising from variances and fluctuation in the body's natural circadianrhythms. Further, these methods ensure that less of a drug is in thebloodstream when disease and addiction symptoms are at there lowest.This minimizes negative side effects, and increases efficacy of thedosing regimen.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an exemplary device useful for implementing the presentinvention;

FIG. 2A and FIG. 2B illustrate comparative drug release profilesdemonstrating operation of the present invention;

FIG. 3 is a schematic illustration of a drug delivery device inaccordance with the present invention;

FIG. 4 is a schematic illustration of an alternative drug deliverydevice in accordance with the present invention

FIG. 5 shows an exemplary administration profile for a stimulantdelivery system;

FIG. 6 shows an exemplary administration profile for a nicotine deliverysystem;

FIG. 7 shows an exemplary administration profile for a nitroglycerinedelivery system tailored to treat variant angina attacks; and

FIG. 8 illustrates an exemplary administration profile for anitroglycerine delivery system tailored to treat stress-induced anginaattack.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The reality of circadian rhythms in animals including humans is wellknown. Biological rhythms are periodic fluctuations in biologicalcharacteristics over time, which also include circadian as well asseasonal variations. Circadian, or approximately 24-hour, rhythmsinclude the production of biological molecules such as cortisol andadrenaline, the regulation of body temperature and heart rate, changesin characteristics of blood, such as stickiness, and behaviors such aswakefulness, sleep and periods of activity.

Research demonstrates that certain disease symptoms follow a dailypattern, with peak symptoms at certain times of the day. It has beenwidely acknowledged that hormones, neurotransmitters and otherintra-body compounds are released in different amounts at differenttimes of the day pursuant to daily patterns. It is believed that thefailure of current transdermal systems to synchronize drugadministration with the body's natural rhythms often lead to (i) severeside effects, including debilitating sleep disorders (in the context ofnighttime nicotine administration, for example), (ii) ever increasingtolerance (in the case of nitroglycerin and other pharmaceuticals forexample), (iii) more expensive therapies, since more of a compound isneeded since body rhythm tailored dosing is not implemented. Inaddition, many addictions follow a daily pattern consistent with one'scircadian rhythms. For example, according to studies performed,immediately upon waking, smoker's have peak nicotine cravings. Thesepeak cravings return after each meal, due to the interplay of serotoninrelease as a trained response to the culmination of a meal. Our methodsprecisely time the administration of drugs so that they reach peaklevels when symptoms are likely to be at their worst, and efficacy isgreatly improved.

The present invention involves precisely timing the administration ofdrugs so that they reach peak levels in synchronization with times whensymptoms are likely to be at their worst, or times at which the drugsare believed to be more effective in the body and/or better tolerated bythe patient. The present invention is described in terms of a particularexample drug delivery system that provides automated and precise controlover dosing, with single-dose capability, (once while people sleep) orcapability to administer separate and varying-sized doses many timesthroughout a multiple day period. The particular implementation isconsistent with a commercial development of a miniaturized, automatedand programmable non-invasive drug delivery system called theChronoDose™ system being developed by the assignee of the presentinvention. The system enables controlling of the amount of drug exposedto the skin in a controlled time dependent way according to a programmedadministration schedule that implements a desired dosage profile. Inthis manner the present invention enables one to precisely control andvary the time of drug release and the amount of each dose, pursuant toan easily set pre-programmed dosage profile.

Research demonstrates that for certain symptoms, conditions anddiseases, drug effects can be optimized when administered in a defined(and often varying) dosage at predefined times. This is known asChrono-Pharmacology. To illustrate the importance of Chrono-Pharmacologyconsider the following facts:

-   -   Asthma attacks are 100 times more likely between 4:00 and 6:00        AM.    -   Heart attacks and strokes are most likely to occur around 6:00        AM.    -   Variant Angina attacks occur30 times more often in the middle of        the night between 2:00 AM and 4:00 AM.    -   Smokers experience the highest cravings immediately upon waking        up    -   Lethargy and difficulty getting out of bed is highest        immediately upon waking up early in the morning    -   Cold and flu symptoms peak during night time and early morning        hours, when cold medications are wearing off

In accordance with the present invention, substances with proven orsuspected chrono-pharmacological efficiency are integrated into aminiaturized, automated, programmable watch-like device, such as device100 shown in FIG. 1. The delivery system 100 shown in FIG. 1 can be usedfor a variety of active compositions, and is small, fully automated andprogrammable. This system consists of a re-usable wristwatch-like device101 to control the time and dosage of drug delivery; and a small,disposable, ‘reservoir’ 103, which is about the size of a quarter or ½dollar coin in a particular example, that the user can simply pop-in toplace on the watch-like platform. This reservoir patch lasts, forexample, up to 72 hours, depending on the application. Shorter andlonger reservoir lifetimes are contemplated. The device is readilyadapted to be worn on the forearm, ankle, or other convenient bodylocation.

In a particular application the replaceable reservoir can include adescription of an administration schedule that can be used to manuallyor automatically program device 100 with an administration schedule. Forexample, written schedule can be printed on or affixed to the reservoir101 or electrically programmed using volatile or non-volatile memory. Inthis manner a dosing profile can be prescribed and filled by a pharmacyin much the same manner as a conventional drug prescription is handledtoday.

An exemplary implementation shown in FIG. 3 comprises a collapsible drugreservoir, an expandable waste reservoir, a micro-pump, electronics forautomation, a display, and a highly permeable membrane. An exemplarysystem is described in a PCT application No. PCT/IB2004/002947entitledTRANSDERMAL DRUG DELIVEDRY METHOD AND SYSTEM filed on Sep. 13, 2004which is incorporated herein by reference. The drug reservoir willcontain about 3 ml of drug formulation. A tiny, miniaturized pump isactivated at pre-programmed times and releases a pre-defined amount ofdrug formulation into the drug chamber, where the formulation comes intocontact with highly permeable membrane. This membrane rests on the skin,and provides for even diffusion of the drug over the device's drugabsorption surface area. This membrane works effectively with, and canbe coated with, an adhesive. In operation, when the administration ofthe drug needs to be discontinued, the remaining drug formulation iseither removed from the membrane area via a waste chamber, containing ahydrophilic substance (hydrogel) or the device is taken off.

In an implementation shown in FIG. 4, a pressurized drug reservoir isused which minimizes or eliminates need for a micropump. Electronicscontrol a valve that allows controlled quantities of the drug to beapplied to the drug chamber where the formulation comes into contactwith highly permeable membrane.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is known. See, for example, U.S. Pat. No.5,370,635 entitled “DEVICE FOR DELIVERING A MEDICAMENT” the disclosureof which is incorporated herein by reference. Such patches may beconstructed using a saturated media, pressurized reservoirs, orunpressurized reservoirs with micropumps for continuous, pulsatile, oron-demand delivery of an active material. For example, apharmaceutically acceptable composition of an active material may becombined with skin penetration enhancers including, but not limited to,oleic acid, amino acids, oleyl alcohol, long chain fatty acids,propylene glycol, polyethylene glycol, isopropanol, ethoxydiglycol,sodium xylene sulfonate, ethanol, N-methylpyrrolidone, laurocapram,alkanecarboxylic acids, dimethylsulfoxide, polar lipids,N-methyl-2-pyrrolidone, and the like, which increase the permeability ofthe skin to the active material and permit the active material topenetrate through the skin and into the bloodstream. Pharmaceuticallyacceptable compositions may be combined with one or more agentsincluding, but not limited to, alcohols, moisturizers, humectants, oils,emulsifiers, thickeners, thinners, surface active agents, fragrances,preservatives, antioxidants, vitamins, or minerals. Pharmaceuticallyacceptable compositions may also be combined with a polymeric substanceincluding, but not limited to, ethylcellulose, hydroxypropyl cellulose,ethylene/vinylacetate, polyvinyl pyrrolidone, and the like, to providethe composition in gel form, which may be dissolved in solvent such asmethylene chloride, evaporated to the desired viscosity, and thenapplied to backing material to provide a patch. The backing can be anyof the conventional materials such as polyethylene, ethyl-vinyl acetatecopolymer, polyurethane and the like.

Example substances include caffeine and a variety of over-the-counterand prescription stimulants (for treating fatigue, sleep disorders,attention deficit disorders and a variety of other conditions), nicotine(for smoking cessation), nitroglycerin (for treating heart attack andstrokes), fentanyl (for treating chronic pain), albutamol (for treatingasthma), and selegiline (for treating depression, attention deficitdisorder or Parkinson's disease). We have carefully identified thesespecific drugs and diseases because they have the following attributes:(i) Chrono-Pharmacology is critical to optimized dosing but is not beingimplemented because no automated transdermal system exists, and (ii)these drugs can be transdermally absorbed passively (i.e., without theneed for ultrasound or electrical stimulation or other permeationenhancers). Exemplary chrono-pharmacological systems that can make useof the present invention are summarized in Table 1 DISEASES/ CONDITIONCHRONOPHARMACOLOGY Morning Adrenaline is lowest in the morning, makingwaking Lethargy uncomfortable and difficult for many people. This can betreated by administering OTC Stimulant before waking Smoking Nicotine atnight creates sleeping disorders Cessation (nightmares), but cravingsare the highest after waking up. This can be treated by administeringNicotine before waking up. Angina Angina (variant) attacks occur 30(thirty) times more often between 2:00 a.m. and 4:00 a.m. This can betreated by administering larger nitroglycerin doses in early morningAsthma Asthma attacks are 100 times more likely between 4:00 a.m. and6:00 a.m. Adrenaline and Cortisol are virtually absent at night. Thiscan be treated by administering albutamol in early morning ColdsHeaviest symptoms overnight and in the morning. This and Flu can betreated by administering Cold/Flu medicine during the night. Heart Heartattacks and strokes are most likely between Attacks 6:00 a.m. and Noon.This can be treated by adminis- and tering Anticoagulants before wakingup. Strokes Pain Neurological pain is worst between 3 A.M and 8 A.M.This can be treated by administering pain medication during sleep.Depression Selegiline at night can create sleeping disorders(nightmares), but depression symptoms are high immediately upon wakingup. This can be treated by administering Selegiline before waking up.Rheumatoid Worst upon awakening. Cortisol and anti-inflammatoryArthritis hormones are very low at night This can be treated byadministering medication delivered before waking up. SupplementsVitamins and supplements are best administered in low doses over thecourse of the day to be most effective.

Using this system the present invention can pre-program the times andamount of each dosage by precisely controlling the amount of drugexposed to the skin during each dosing. This feature is advantageouswhen a drug is best administered during sleep, e.g., 1 to 2 hours beforewaking up. The present invention precisely counteracts peak diseasesymptoms and increase patient compliance.

The present invention represents the first true non-invasivechrono-pharmacological drug delivery device. While current transdermalapplications are restricted to the dosage profile shown in FIG. 2 a, theautomated implementation of the present invention can be programmed fora variety of drug delivery patterns to achieve customized patient dosingregiments for optimal therapy (FIG. 2 b). There are many advantages fora controlled transdermal release of an active material such as a drug.As used herein, the term ‘controlled’ or ‘sustained’ release of anactive material includes continuous or discontinuous, linear ornon-linear release of the active material according to a programmedschedule. Among the advantages of controlled release are the convenienceof a single application for the patient, avoidance of peaks and valleysin systemic concentration which can be associated with repeatedinjections, the potential to reduce the overall dosage of the activematerial, lower body stress, and the potential to enhance thepharmacological effects of the active material. A lower, sustained dosecan also prevent adverse affects that are occasionally observed withinfusion therapy. In addition to significantly reducing the cost ofcare, controlled release drug therapy can free the patient from repeatedtreatment or hospitalization, thus offering the patient greaterflexibility and improving patient compliance. A controlled releaseformulation of certain drugs also provides an opportunity to use thedrug in a manner not previously exploited or considered. The presentinvention is particularly advantageous when (i) knownchrono-pharmacological information shows that a drug's effects canoptimized when administered in a defined dosage at a predefined time ortimes, and/or (ii) patient compliance with the dosing regimen is greatlyincreased due to automation, (doses required at inopportune times, whensleeping, for example).

Applications—ArisePatch™

A contemplated consumer product is the ArisePatch™. Most peopleexperience difficulty and discomfort when waking early in the morning.According to a 2002 National Sleep Foundation poll 49% of US adults age18-29 have trouble waking in the morning and 41% of US adults age 30-64have trouble waking in the morning. There are 165,000,000 adults in theUS alone age 18-64, meaning approximately 74,250,000 US adults age 18-64have trouble waking in the morning.

The ArisePatch implementation of the present invention allowsindividuals, while asleep, to have an over-the-counter (OTC) orprescription stimulant automatically administered during a 1-2 hourpre-wake-up period. FIG. 5 illustrates an exemplary stimulantadministration profile showing a blood plasma level of ephedrine innanograms per milliliter on the vertical axis, with time on thehorizontal axis. Stimulant concentrations will reach peak levelsimmediately prior to having to wake. Immediately upon waking up theindividual will be alert and feel well rested. The ArisePatch™ willeliminate the typical discomfort or difficulty associated with gettingup early. This functionality is attractive to employed people getting upfor work to ensure punctuality, and just about anyone who wants tooffset morning discomfort associated with a late night, jet lag, orsickness.

Applications—Smoking Cessation

Nicotine replacement has been the most frequently used therapy tosupport smokers in their effort to quit. Smokers report that the cravingfor a cigarette is greatest immediately upon waking in the morning. Thetime elapsed between wakening and the first cigarette is the bestindicator of addiction. For most smokers this time only a few minutes.

Current nicotine patches cause severe sleep disturbances by releasingnicotine steadily throughout the night to ensure sufficient morningnicotine levels to offset the strong morning craving. It is widelyaccepted that current nicotine patches have a detrimental and commonside effect—sleeping disorders, and insomnia, including persistentnightmares. Therefore, users are often forced to remove the patch in theevening before they go to bed. This eliminates sleep disturbances, butresults in nicotine levels that are insufficient to offset the strongmorning craving. This is a major drawback to current nicotine patchesand many users relapse, resulting in a less efficient smoking cessationtherapy. Current patches present the user with a difficult decision,choosing between nightmares and relief from the strong morning cravings.

An exemplary product contemplated by the present invention is calledNicotine ChronoDose™ system. In accordance with the present invention,the system can begin to administer nicotine(or nicotine analogs or anyother smoking cessation compound including but not limited to Zyban)automatically during a one hour period immediately prior to waking. Thiswill relieve the smoker's peak craving upon waking without causingnightmares and insomnia. We believe that this system clearly provides asuperior method for smoking cessation.

A more advanced nicotine replacement system than that described above isworn for three days at a time and is programmed to release nicotine in adaily rhythmic pattern such as shown in FIG. 6 to offset peaks in asmoker's cravings. FIG. 6 illustrates an exemplary nicotineadministration profile showing a blood plasma level of nicotine innanograms per milliliter on the vertical axis, with time on thehorizontal axis. This implementation will reduce nicotine dependency byadministering pre-programmed levels of nicotine pursuant to typicalsmoking patterns. For instance many smokers report that cravings for acigarette are greatest upon waking up, after lunch, mid afternoon, afterdinner and before bedtime. This implementation of the present inventionwill automatically release larger doses of nicotine to offset peakcravings and no nicotine when cravings are typically at a minimum. Thepresent invention may be delivered in a pre-programmed manner for eachtreatment regimen. The only involvement by the user will be thereplacement of the ‘reservoir’ every three days, and the replacement ofthe platform housing as needed.

This implementation represents a tremendous move forward in nicotinereplacement therapy, and is far superior to the old-technology systemsthat simply release the same amount of nicotine all day and night. Withthe present invention, one can systematically decrease a smoker'stolerance without increasing dependence (the result of a constant flow)and better wean a smoker off nicotine. This will allow the smoker tobetter ‘tailor-down’ and decrease the amount of nicotine he needs toquit. Modern smoking cessation is much more than nicotine replacementtherapy. Programs also include weight control, diet and psychologicalsupport. The present invention fits well into these programs, since itaddresses the key component of being able to quit smoking by efficientlycountering the withdrawal symptoms while doing away with the negativeside effects of current nicotine replacement therapy systems, namelysleep disturbance.

Applications—Cold and Flu treatment

Cold and flu symptoms are worst from midnight until the early morningbecause the concentration of cortisol is lowest at that time. Currentnight time cold and flu medication end up losing efficacy by earlymorning when cold and flu symptoms are highest. Therefore peoplesuffering from a cold or flu are often unpleasantly awoken by anincrease in symptoms, cutting sleep short. Set and put on beforebedtime, the present invention will automatically deliver a larger doseof medication and immuno-boosters in the early morning hours to moreeffectively combat the peak cold and flu symptoms that occur in themorning. Users will experience less severe cold and flu symptoms duringthe morning hours, will not have their sleep cycle cut short, and willwake up feeling symptom-free. This implementation uses prescription orOTC cold medicine alone or optionally in combination with certaintransdermally efficacious vitamins and immune system boosters to providea total solution to cold and flu ailments. This is the first coldtherapy that combines OTC medicine with supplemental immuno-boosters ina comprehensive and automated manner. Our system will treat the coldsymptoms directly and boost the body's immune system to help it healnaturally.

In a particular application, the Cold and Flu automated transdermal drugdelivery system utilizes OTC cold medicine, Vitamin C, Echinacea, andZinc to provide a total solution to cold and flu ailments, and all whileyou sleep. Cold and flu symptoms are worst in the middle of the nightand early morning because the hormone cortisol, a key inflammationfighter, is missing at that time. Cold and flu symptoms are worst frommidnight until the early morning because the concentration of cortisolis lowest at that time. Current night time cold and flu medication endup losing efficacy by early morning when cold and flu symptoms arehighest. Therefore people suffering from a cold or flu are oftenunpleasantly awoken by an increase in symptoms, cutting sleep short

Set and put on before bedtime, the Cold and Flu automated transdermaldrug delivery system utilizes our proprietary technology toautomatically deliver a larger dose of medication and immuno-boosters inthe early morning hours to more effectively combat the peak cold and flusymptoms that occur in the morning. Users will experience less severecold and flu symptoms during the morning hours, will not have theirsleep cycle cut short, and will wake up feeling symptom-free.

Our system not only combats statistically proven peak nighttime andearly morning cold symptoms by releasing OTC cold medicine, but actuallyhelps your body to heal by boosting its immune system through Vitamin C,Echinacea and Zinc supplementation in small but distinct doses all nightlong.

Our Cold/Flu system releases these combination of compounds every 2hours throughout the night, with a higher dosage of compounds beingreleased in the morning to combat these proven middle of the night andearly morning symptoms, which are the worst of the day.

Cold and flu symptoms are worst in the middle of the night and earlymorning because the hormone cortisol, a key inflammation fighter, ismissing at that time. Our system utilizes its core competitive advantageby pre-programming our System to release more medicaments precisely atthat time to offset these peak symptoms. Current cold and flumedications end up losing efficacy by early morning when cold symptomspeak, so the user either has sleep cut short due to the onset of thesesymptoms, or wakes up out of slumber feeling sick with peak symptoms.Our system will ensure that a while a person is actually sleeping, asufficient dose of cold and flu medicine is freshly delivered to offsetthese peak morning symptoms.

Applications—Weight Control, Vitamin and Herbal Supplementation

In yet another application, a series of weight loss vitamins andsupplements is administered in small distinct doses many times over amultiple day period. Vitamins and supplements are absorbed by the bodyin small dosages. Contrary to popular belief, once-a-day products arenot maximally effective because excess dosages are excreted unused. Thisimplementation of the present invention precisely controls the timingand dosage of small but distinct amounts of vitamins and supplementsduring a 24 hour period to ensure that vitamins and supplements areconstantly bio-available for optimal absorption and cellular function.Greater doses are automatically released prior to mealtimes to counterappetite cravings, resulting in a much more effective diet program.

Applications—Angina

Research shows that variant angina occurs 30 times more often between2:00 a.m. and 4:00 a.m. (‘critical angina phase’) than at any other timeof the day. Nitroglycerin effectively combats angina attacks, ifadministered in optimal doses. Current nitroglycerin patches exist, butthey can only release a constant amount of nitroglycerine steadily overtime. Current patches cannot tailor the release of nitroglycerine tooptimize treatment by releasing more nitroglycerine precisely during thecritical angina phase to offset these peak symptoms.

In addition, nitroglycerine loses its effectiveness and requires higherand higher dosages when administered constantly. Our bodies becometolerant to it. Current systems cannot stop or decrease the release ofnitroglycerine when disease symptoms are lowest. Thus, these current‘dumb’ patches cannot offset the critical angina phase by releasing moreof the drug, nor can they shut down or stop nitroglycerineadministration when the body doesn't need it. It is a ‘one dose fitsall’ type of scenario once each “dumb” patch is applied to the patient.

The method in accordance with the present invention utilizes anautomated transdermal system in order to transdermally administer morenitroglycerine during the critical angina phase to ensure adequateoffset of these symptoms and less nitroglycerine when it is not neededso that no tolerance builds up. Our method utilizes a ‘smart’ patchmedicine system at this time to offset these peak critical phases in thedisease cycle arising due to the human body's circadian rhythm.

The preprogrammable automated transdermal system is worn around thewrist like a watch (or the forearm arm or ankle) and releasesnitroglycerine in optimal dosages at times that are optimallysynchronized. This is pursuant to a pre-programmed and tailored dosageprofile. Current nitroglycerin patches only have the capability torelease a constant dose of nitroglycerin over a period of time. Currentnitroglycerin patches simply cannot alter or vary dosages to increasedosages at different times of the day, and decrease dosages at othertimes of the day.

The nitroglycerin system in accordance with the present invention hasthree primary advantages over current nitroglycerin patches. First, thesystem utilizes its core competitive advantage to automatically andprecisely release nitroglycerin in peak amounts to offset the peaksymptoms of morning attacks occurring during the critical angina phase.Current nitroglycerine patches have release rates that stay constant anddo not increase to offset critical phases, and do not decrease assymptoms decrease. Second, our system solves the tolerance issue byreleasing less (or no) nitroglycerin in off-peak hours, and thenreleasing nitroglycerin at just the right time so that it is presentduring critical periods, without increasing tolerance. Third, our systemaccomplishes 1 and 2 above automatically, without the need for a patientto wake up to take a drug at this critical phase, which does away withthe need for any increased patient compliance.

As a result we believe that our nitroglycerin system represents an idealdelivery system for patients who use nitroglycerin regularly for thetreatment and/or the prevention of heart attacks and strokes. Patientcompliance regarding the timing and dose of heart attack medication iscrucial. Patient non-compliance with physician's instructions for thisis often a cause of re-hospitalization, according to the US Departmentof Health and Human Services. The system solves this problem, and willdecrease the need for re-hospitalization by dramatically increasingpatient compliance.

This system can be either an ‘wear each night and remove in the morning’system, whereby it only releases nitroglycerine automatically to offsetthe critical angina phase in the morning, or a ‘total solution’ system,that is worn for a period of 24 hours to several days, and thatadministers nitroglycerine in tailored amounts and at tailored times assynchronized with the body's circadian rhythm (and conveniently takenoff while showering or swimming).

The system is an innovative new drug therapy for angina. With itssuperior advantage of optimized and automated time and doseadministration synchronized with our circadian rhythms, the system inaccordance with the present invention ensures that nitroglycerin willcirculate in the bloodstream exactly when the patient needs it, andwithout any build up tolerance. For these reasons, our system issuperior to current steady release nicotine patches. Our system'sincreased advantages are extremely relevant for those patients withmoderate to severe angina.

FIG. 7 shows an exemplary administration profile for a nitroglycerinedelivery system tailored to treat variant angina attacks or anginapectoris. This type of angina attack has a peak frequency in manypatients between the hours of 2:00 and 4:00 AM. This is a particularlydifficult time to wake up to take a drug such as nitroglycerine. Inaccordance with the present invention an administration profilesubstantially like that shown in FIG. 7 is automatically administered.In FIG. 7 the vertical axis indicates blood plasma level in nanogramsper milliliter, and the horizontal axis indicates time from 10:00 PMthrough the night to 8:00 AM.

FIG. 8 illustrates an exemplary administration profile for anitroglycerine delivery system tailored to treat stress-induced anginaattack. In FIG. 8 the vertical axis indicates blood plasma level innanograms per milliliter, and the horizontal axis indicates time from12:00 AM through the day until about 4:00 PM. The administration profileshown in FIG. 8 provides a high blood plasma concentration throughoutthe waking hours of a day when stress is likely occur.

Applications—Asthma

The automated transdermal asthma system automatically administers amorning dose of albuterol, tolobuterol, salmeterol, beta 2 agonist orany other antiarrhythmic drug (an ‘Asthma drug’) to combat the peaksymptom of morning asthma attacks known as the ‘morning dip’.

Asthma attacks occur 100 (one hundred) times more often between thehours 4 A.M. and 6 A.M., when most people are asleep. This is due to theearly morning deterioration of respiratory function known as ‘morningdip’, which is the time of day that respiratory function is at itslowest. These early morning asthma attacks cause great distress tosufferers and care providers. The morning dip represents the dip inrespiratory function at this time when asthma attacks are 100 times morelikely to occur. Our system effectively combats the morning dip byreleasing more Asthma drug at this time to offset this peak morningsymptom . In other words, our ‘smart’ patch varies the level of drug inthe bloodstream so that drug concentrations are highest when respiratoryfunction is at its lowest.

Current ‘dumb’ asthma patches exist, but they can only release aconstant amount of drug steadily over time. Current patches cannottailor the release of drug to optimize treatment by releasing more drugprecisely during the morning dip to offset these peak critical symptoms.

The Asthma system has two primary advantages over current patches.First, the system of the present invention utilizes its core competitiveadvantage to automatically and precisely release albuterol or otherasthma drugs in peak amounts to offset the peak symptoms associated withthe morning dip. Current patches have release rates that stay constantand do not increase to offset this peak critical phases, and do notdecrease as symptoms decrease. Second, our system accomplishes 1 and 2above automatically, without the need for a patient to wake up to take adrug at this critical phase, which does away with the need for anyincreased patient compliance.

The automated transdermal system for Asthma is worn around the wristlike a watch (or the forearm arm or ankle) and releases albuterol orother Asthma drugs in optimal dosages at times that are optimallysynchronized, especially to offset the morning dip, pursuant to apre-programmed and tailored dosage profile. Current Asthma patches onlyhave the capability to release a constant dose over a period of time.Current Asthma patches simply cannot alter or vary dosages to increasedosages at different times of the day, and decrease dosages at othertimes of the day.

The system is an innovative new drug therapy for asthma. With itssuperior advantage of optimized and automated time and doseadministration synchronized with our circadian rhythms, our systemensures that albuterol or another asthma drug will circulate inincreased amounts in the bloodstream exactly when the patient needs it.For these reasons, our system is superior to current steady releasepatches. Our system's increased advantages are extremely relevant forthose patients with moderate to severe asthma.

Applications—Hypertension

The clondine automated transdermal system utilizes clondine, (or anotherhypertension drug) an effective drug that combats high blood pressure.The clondine automated transdermal drug delivery system has an automatedmorning release of Clondine to combat the peak symptom of morning heartattacks.

Blood pressure differs at different times of the day. Blood pressuresurges upon waking, and is lower by 20 to 30 per cent while sleeping.Our preprogrammed automatic transdermal system utilizes its corecompetitive advantage by releasing clondine in a tailored fashion tocounter high blood pressure when symptoms are highest, while releasingless clondine when symptoms are less severe.

Current clondine patches release the drug consistently over time. Itcannot release more of the drug when symptoms are worst. People die mostwhen the symptoms peak. Having the advantage of administering more ofthe drug when a patient needs it the most can mean the differencebetween life and death, especially in patients with moderate to severehigh blood pressure.

The automated transdermal system for hypertension has two primaryadvantages over current patches. First, our system utilizes its corecompetitive advantage to automatically and precisely release clondine orother hypertension drugs in peak amounts to offset the peak symptomsassociated with the dangerous morning symptoms. Current hypertensionpatches have release rates that stay constant and do not increase tooffset this peak critical phases, and do not decrease as symptomsdecrease. Second, our system accomplishes 1 and 2 above automatically,without the need for a patient to wake up to take a drug at thiscritical phase, which does away with the need for any increased patientcompliance.

Applications—Depression, Alzheimer's, Attention Deficit

The selegiline automated transdermal system utilizes selegiline, aneffective MAO inhibitor for the treatment of depression, Alzheimer's andAttention Deficit Disorder.

The selegiline automated transdermal drug delivery system gives anautomated morning release of selegiline to combat the peak symptom ofmorning depression without the side effect of sleep disturbances.

The system in accordance with the present invention is applied beforebed. It does not release the drug until an hour or 2 before morning, sosymptom of morning depression would be corrected by our system withoutsubjecting the patient to sleep disturbances.

Primary negative side effects of the selegiline patches are abnormaldreams, insomnia, and difficulty sleeping. We believe that byspecifically refraining from administering selegiline at night, andutilizing our system's core competitive advantage to turn it on an houror so before waking, we can do away with this negative side effect andstill offset the critical phase of morning symptoms of depression. Ithas been reported that patients have increased symptoms of depressionupon waking if the critical amount of Selegiline is not circulatingthrough their system. Our system utilizes its core competitive advantageto provide a compelling solution to this problem. Our system is appliedbefore bed, it would not release the drug until an hour or two beforemorning, so symptom of morning depression would be corrected by oursystem without subjecting the patient to sleep disturbances

Current Oral Selegiline produces horrible side effects. There is a newSelegiline patch coming out on the market, but it to produces sleepdisturbances. It is believed that the system in accordance with thepresent invention would be superior to conventional Selegiline productdelivery systems.

Applications—In General

The present invention is particularly useful in applications in which itis necessary and/or desirable to start the administration of a drug,stop the administration of a drug, and/or increase/decrease the dosageof a drug at a time when it is inconvenient or impossible for a patientto initiate the necessary actions. This is particularly useful for awide variety of drug administration applications that benefit whenadministration is started, stopped, or changed while a person issleeping. As chronotherapy knowledge increases, it is contemplated thata wide variety of applications will be discovered in which benefit isrealized by starting, stopping and/or changing the drug administrationwhile a patient sleeps.

In each of the examples, treatment is continued as needed to providesuperior symptomatic relief, prevent exacerbation of symptoms, and/orprevent and/or delay progression of the disease state or condition inthe patient, or until it is no longer well tolerated by the patient, oruntil a physician terminates treatment. For example, a physician maymonitor one or more symptoms and/or serum levels of active materialand/or metabolic by-product(s) in a patient being treated according tothis invention and, upon observing attenuation of one or more symptomsfor a period of time, conclude that the patient can sustain the positiveeffects of the above-described treatment without further administrationfor a period of time. When necessary, the patient may then return at alater point in time for additional treatment as needed.

As used herein, ‘day’ means a 24-hour period. Thus, for example, ‘for atleast three consecutive days’ means for at least a 72-hour period.During or after the treatment, a physician may monitor one or moresymptoms and/or serum levels in the patient and, upon observing animprovement in one or more of the parameters for a period of time,conclude that the patient can sustain the positive effects of thetreatment without further administration of the active material for aperiod of time.

In order to use an active material for therapeutic treatment (includingprophylactic treatment) of mammals including humans according to themethods of this invention, the active material is normally formulated inaccordance with standard pharmaceutical practice as a pharmaceuticalcomposition. According to this aspect of the invention there is provideda pharmaceutical composition comprising an active material inassociation with a pharmaceutically acceptable diluting substance orcarrier, wherein the active material is present in an amount foreffective treating or preventing a particular condition. Whileindividual needs may vary, determination of optimal ranges for effectiveamounts of an active ingredient (alone or in combination with otherdrugs) within the ranges disclosed herein is within the expertise ofthose skilled in the art. Accordingly, ‘effective amounts’ of eachcomponent for purposes herein are determined by such considerations andare amounts that improve one or more active ingredient functions and/orameliorate on or more deleterious conditions in patients and/or improvethe quality of life in patients.

The present invention also provides pharmaceutical kits for treating aparticular symptom, condition and/or disease and/or improving aparticular biological function, comprising one or more containerscomprising one or more active compositions in accordance with thisinvention. Such kits can also include additional drugs or therapeuticsfor co-use with the active composition for treatment or prevention of aparticular symptom, condition and/or disease and/or improving aparticular biological function . In this embodiment, the activecomposition and the drug can be formulated in admixture in onecontainer, or can be contained in separate containers for simultaneousor separate administration. The kit can further comprise a device(s) foradministering the compounds and/or compositions, such as device 100shown in FIG. 1, and written instructions in a form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which instructions can alsoreflect approval by the agency of manufacture, use or sale for humanadministration.

Although the invention has been described and illustrated with a certaindegree of particularity, it is understood that the present disclosurehas been made only by way of example, and that numerous changes in thedosages, administration profiles, timing, as well as the combination andarrangement of parts can be resorted to by those skilled in the artwithout departing from the spirit and scope of the invention, ashereinafter claimed.

1. A method for delivering a bioactive agent to a human or animalcomprising: providing a transdermal drug delivery device coupled to thehuman or animal, the delivery device having a source of the bioactiveagent, a programmable timing mechanism, and a mechanism for causing thebioactive agent to be delivered transdermally in response to the timingmechanism; and timing routines implemented by the timing mechanism,wherein the timing routines are selected to deliver the bioactive agentat a time, rate, sequence and/or cycle that is synchronized with abiological rhythm of the human or animal.
 2. The method of claim 1wherein the bioactive agent comprises a stimulant and the timingroutines are selected to deliver the stimulant immediately before thehuman or animal wakes up.
 3. The method of claim 1 wherein the bioactiveagent comprises nicotine and the timing routines are selected to deliverthe nicotine at times that are associated with nicotine cravings.
 4. Themethod of claim 3 wherein at least one of the selected times correspondsto a time at which the human or animal experiences a morning nicotinecraving.
 5. The method of claim 1 wherein the bioactive agent comprisesan antihistamine and the timing routines are selected to deliver theantihistamine while the human or animal sleeps.
 6. The method of claim 1wherein the bioactive agent comprises a stimulant and the timingroutines are selected to deliver the stimulant immediately before thehuman or animal wakes up.
 7. A method for treating a symptom, condition,and/or disease comprising: identifying a drug suitable for treating aparticular symptom, condition and/or disease; identifying a biologicallysuperior time for administering a drug; programming a time-programmabletransdermal drug delivery system with a schedule selected to synchronizewith the identified biologically superior time; and causing thetime-programmable transdermal drug delivery system to deliver the activeingredient according to the programmed schedule.
 8. A programmabletransdermal drug delivery device comprising: an interface for couplingto the skin of a host; a reservoir storing a quantity of an activecomposition; valve mechanism for supplying a quantity of the activecomposition from the reservoir to the interface in response to a controlsignal; and a timing mechanism coupled to the valve mechanism andconfigured to generate the control signal according to a programmedadministration schedule.
 9. The device of claim 7 wherein the valvemechanism controls a rate at which the active composition is supplied inresponse to the control signal.
 10. The device of claim 7 furthercomprising a mechanism for removing the active composition from theinterface in response to the control signal.
 11. The device of claim 7further comprising a mechanism for removing carrier materials from theinterface.
 12. A kit comprising a first container comprising apharmaceutical formulation of an active material, said formulationcomprising an amount of active material effective to treat a symptom,condition, and/or disease, wherein said first container is adapted tocoupled to a programmable transdermal drug delivery system.
 13. The kitof claim 11 wherein the first container includes a specification of anadministration schedule that is used to program the programmabletransdermal drug delivery system.
 14. A method for delivering a drug toa human or animal comprising: providing a transdermal drug deliverydevice coupled to the human or animal, the delivery device having asource of the drug, a programmable timing mechanism, and a mechanism forcausing the drug to be delivered transdermally in response to the timingmechanism; and timing routines implemented by the timing mechanism,wherein the timing routines are selected to deliver the drug at a timewhen the human or animal is expected to be asleep.
 15. The method ofclaim 13 wherein the timing routines initiate drug delivery at a timewhen the human or animal is expected to be asleep.
 16. The method ofclaim 13 wherein the timing routines terminate drug delivery at a timewhen the human or animal is expected to be asleep.
 17. The method ofclaim 13 wherein the timing routines increase the dosage of drugdelivered at a time when the human or animal is expected to be asleep.18. The method of claim 13 wherein the timing routines decrease thedosage of drug delivered at a time when the human or animal is expectedto be asleep.